2-Oxazolidinones 2 -oxazolone

Anodic oxidation of the carbamates 17 and 23 in methanol, followed by reaction with chlorodiphenylphosphine affords the a-diphenylphosphinylcarbamates 20 and 25, from which the readily generated carbanions react with aldehydes to give the 4-phosphinyl-2-oxazolidinones 21 and 26. The removal of the diphenylphosphinyl group by a mild thermal treatment provides a route to the 2(3//)-oxazolones 22 and 27 (Fig. 5.6). ... 

Treatment of the a-methoxycarbonylbenzyl carbamate 34 with diisobutylalumi-num hydride (DIBAL-H), followed by dehydration of the resulting 4-hydroxy-2-oxazolidinone 35 with NH4CI gives the 5-phenyl-2(37f)-oxazolone 36 (Fig. 5.8). ... 

Both 4-hydroxy- and 4-methoxy-2-oxazolidinones are routinely employed as good synthetic precursors for 2(3/ )-oxazolones. 

Anodic oxidation of 2-oxazolidinones 81 in methanol using Et4N" OTs as a supporting electrolyte yields the 4-methoxylated derivatives 82 that undergo a facile elimination of methanol to give 2(3//)-oxazolones such as 83 and 84. ... 

Treatment of 4-methoxy-2-oxazolidinone 86 with indolylmagnesium bromide 87, followed by A-protection with a ferf-butoxycarbonyl (Boc) group affords NJd -di-Boc-4-(3-indolyl)-2-oxazolidinone 88. Subsequent treatment with A-bromosuc-cinimide (NBS) in the presence of azobisisobutyronitrile (AIBN) followed by electrochemical reduction yields the protected 4-(3-indolyl)-2(3//)-oxazolone 90 (Fig. 5.23). The Boc groups are easily removed by pyrolysis."" "" ... 

The addition of hydrazine to diphenylvinylene carbonate 92 quantitatively affords a 1 1 mixture of perhydro-l,3,4-oxadiazin-2-one 93 and 2-oxazolidinone 94 derivatives, both of which are smoothly dehydrated with P2O5 to afford 1,3,4-oxadiazin-2-one 95 and 3-amino-2(3//)-oxazolone 96 (Fig. 5.24), respectively. Addition of primary amines to diphenylvinylene carbonate results in exclusive formation of 3-aIkyl-2(3//)-oxazolones, previously investigated as amino protecting groups in peptide synthesis. 

A 3-acyl-4,5-unsubstituted-2(3//)-oxazolone 157 smoothly undergoes electrophilic addition with Br2 (or NBS) and PhSeCl in methanol to give frani-5-bromo-4-methoxy- and frani-4-methoxy-5-phenylselenenyl-2-oxazolidinones 158, respectively, with full regio- and trans-selectivity (Fig. 5.39). Both substituents thus... 

The RuCl2(PPh3)3 catalyzed addition of polyhalomethanes, CCI4 and CBrCl3, to 3-acetyl-2(37f)-oxazolone 84 leads to the exclusive formation of the tmns-4-halo-5-(trichloromethyl)-3-acetyl-2-oxazolidinones 178." In the presence of a radical... 

The 3-acyl-2(3F/)-oxazolones function as good dienophiles in cycloaddition reactions with cyclic 2,4-dienes such as cyclopentadienes and anthracenes. Thus, the thermal reaction of 3-acetyl-2(37/)-oxazolone with cyclopentadiene and the hexachloro and hexamethyl derivatives gives endo-cycloadducts exclusively. In particular, the chiral cycloadducts 221 and 223 derived from the diastereoselective Diels-Alder reactions of 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazo-lones with hexamethylcyclopentadiene and 9,10-dimethylanthracene, respectively, are highly useful as chiral 2-oxazolidinone auxiliaries. The conformationally rigid roofed structures play a crucial role in affording excellent chiral induction (Fig. 5.54). 

The thermal cycloaddition of 3-acyl-2(3/7)-oxazolones 157 to dialkyl azodicar-boxylates 228 proceeds smoothly under mild conditions (at 80 °C) to give the regiocontrolled cycloadducts 229 exclusively, although two other possible addition modes exist neither diazetidines 230 (1,2-addition) nor isoxazolidines 231 (1,3-addition) are detected. In the case of chiral N-substituents diastereoselectivities of up to 72% de have been obtained. Treatment of the chiral cycloadducts 229 with acidic methanol gives tra i-5-hydrazino-4-methoxy-2-oxazolidmone derivatives 232 that are precursors for a variety of optically active a-amino acids 233 and 2-oxazolidinone auxiliaries 234 (Fig. 5.56 Table 5.10, Fig. 5.57)7 ... 

The ene-reaction, which is mechanistically related to the Diels-Alder reaction, has also been reported. The thermal addition of 3-ferf-butoxycarbonyl-2(3//)-oxazolone 236 to 2,2 -biindole 235 affords 4-(2,2 -biindol-3-yl)-2-oxazolidinone 237, probably via the indoline derivative. The product is further converted to the fused aromatic compound 238 by bromination with NBS and AIBN, followed by dehydrobromination (Fig. 5.58). ... 

Alkoxy-2(3/f)-oxazolones 47 react with aliphatic and aromatic aldehydes in the presence of Lewis acid catalysts to produce alkyl 2-oxazolidinone-4-carbox-ylates 291 ° by successive ring opening and reclosure. 

Dialkoxy-2-oxazolidinones 295, which are prepared by reaction of 5-alkoxy-2(3//)-oxazolones 47 with acetals in the presence of Lewis acid catalysts, are hydrolyzed in the presence of a protonic acid to produce a-amino acid esters 296 (Fig. 5.70 Table 5.11, Fig. 5.71 Table 5.12, Fig. 5.72 Table 5.13, Fig. 5.73 Table 5.14, Fig. 5.74). ... 

TABLE 5.13. SYNTHESIS OF 5,5-DIALKOXY-2-OXAZOLIDINONES FROM 5-ALKOXY-2(3//)-OXAZOLONES"... 

On treatment with phosphorus pentachloride, 4,5-diaryl-2(37/)-oxazolones 297 are reported to afford 5-chloro-4,5-diaryl-2(5//)-oxazolones 298, rather than the expected 2-chloro-4,5-diaryloxazoles. The 5-chloro-products react with methanol to give 4,5-diaryl-4,5-dimethoxy-2-oxazolidinones 299, which are further converted on heating to 4,5-diaryl-5-methoxy-2(5//)-oxazolones 300 (Fig. 5.76). ... 

Dehydration of 4-hydroxy-4,5,5-trimethyl-2-oxazolidinone 301 with a catalytic amount of p-toluenesulfonic acid affords the isomeric dimers 303 and 304 in a ratio of 1 2. The former type of dimer, that is, 303 likely results from coupling of the isomeric 2(5//)-oxazolone 302A with 4-methylene-2-oxazolidinone 302B, which are the initially formed dehydration products. On prolonged heating in CH2CI2, the 2(5//)-oxazolone dimer 303, completely isomerizes to the 4-methylene-2-oxazoh-dinone dimer 304 (Fig. 5.77). " ... 

The tandem condensation of isocyanates with an a-ketol in DMF leads to the 2-oxazolidinone derivatives 308 that are dehydrated to the 2(3//)-oxazolones 309 by refluxing in DMSO (Fig. 5.80). ... 

TABEE 5.11 SYNTHESIS OF ALKYL 2-OXAZOLIDINONE-4-CARBOXYLATES FROM 5-ALKOXY-2(3H)-OXAZOLONES, 43... 

The alkylation of enolates from some recently developed 2-oxazolidinone auxiliaries will be briefly discussed. The Diels-Alder reaction of the enantiomerically pure 3-(apocamphane-carbonyl)-2(3//)-oxazolone 13 with anthracene gives, diastereoselectively, a 97 3 ratio of diastereomeric adducts63. Recrystallization followed by removal of the apocamphanecarbonyl auxiliary and acylation gives the diastereomerically pure enantiomer 14 in good yield. Subsequent enolate formation and alkylation gives highly diastereoselective reactions and easily purified products due to the fact that the major product is readily crystallized. Thus alkylation... 

In this chapter, oxazole and its derivatives are named and numbered as in Chemical Abstracts. Thus compound (6) is called 4,5-dihydrooxazole rather than 2-oxazoline or A2-oxazoline, (7) is 2,5-dihydrooxazole, the betaines (3) are named anhydro-5-hydroxy-oxazolium hydroxides and not oxazolium 5-oxides or oxazolium 5-olates, and the oxo derivatives (4) and (5) are 5(4//)-oxazolone and 5(2//)-oxazolone, respectively, the position of the extra hydrogen atom being indicated in parentheses. The fully saturated compound (8) is oxazolidine its oxo derivatives are named oxazolidinones and oxazolidinediones, e.g. compound (9) is 2-oxazolidinone and (10) is 4,5-oxazolidinedione. A formula such as (11) is not meant to imply that all the substituents are methyl groups it represents a general oxazolidine derivative and is used in place of the cumbersome expression (12 R-R = H, alkyl or aryl). 

The circular dichroism of cis- and trans- 2-oxazolidinones (59 R = H or Me) has been measured (79T2009). Geometrical isomerism round the exocyclic double bond in 4-(aryl-methylene)-5-(4//)-oxazolones (60), the unsaturated azlactones, is a well-studied phenomenon (75S749). It has been shown by X-ray crystallography (74T351) that the stable form of 4-benzylidene-2-phenyl-5(4//)-oxazolone has the (Z) configuration (61). It isomer-izes to the labile (E) form (62) in polyphosphoric acid and the change is reversed in pyridine. 

H)-Oxazolones give hydroxy ketones on alkaline hydrolysis lithium aluminum hydride reacts at the C=N bond to form the corresponding 2-oxazolidinones (Scheme 17). 

The 5(2H)-oxazolones (213) present two sites, C(4) and C(5), to nucleophilic attack they usually react at the latter. The benzylidene derivative (214), the most thoroughly studied member of this class, possesses an additional electrophilic centre at the exocyclic carbon atom. However, alkaline hydrolysis of this compound affords phenylacetamide and benzoylformic acid by acyl-oxygen fission (equation 50). a-Keto acids are also obtained when 2-trifluoromethyl-5(4//)-oxazolones are hydrolyzed, the reaction involving preliminary isomerization to a 5(2//)-oxazolone. The example shown in equation (51) represents the first non-enzymatic synthesis of an optically active a-keto acid. An instance of nucleophilic attack at C(4) of a 5(2//)-oxazolone is the formation of the oxazolidinone (215) in a Grignard reaction (equation 52). However, the typical behaviour of unsaturated pseudooxazolones like (214) is conjugate addition of a nucleophile, followed by further transformations of the resulting 5(4F/)-oxazoIones. This is illustrated by the reaction of compound (214) with benzene in the presence of aluminum chloride to yield, after aqueous work-up, the acylamino acid (216 equation 53). 

The first simple 5(2/f)-oxazolones were the trifluoromethyl derivatives obtained by treating a-amino acids with trifluoroacetic anhydride (equation 156). A general synthesis of 2,2-disubstituted 5(2/f)-oxazolones is the condensation of a- (hydroxylamino) acids with ketones (equation 157) (80S55). The dehydrogenation of 2,2-bis(trifluoromethyl)-5-oxazolidinones affords bis(trifluoromethyl) derivatives (equation 158) (79LA1547). 

D. 3-Aaetyls 3H)-oxazolone. The crude mixture of 3-acetyl 4- and 5-chloro-2-oxazolidinone from Step C is placed in a 2-L, three-necked flask equipped with a thermometer, sealed mechanical stirrer, and gas discharge tube. The material is heated to 120°C with stirring, and the temperature is then slowly increased to 150 C and held there until the evolution of gas ceases (Note 10). The cooled, black reaction mixture is distilled at 20 mm. The fractions boiling up to 150°C are collected and redistilled through a 50-cm x 3-cm Vigreux column fitted with a variable take-off head. There 1s obtained 140-172 g (55-68%) of product, bp 108-U2°C (24 mm), which solidifies, mp 35-37 C (Note 11). 

Oxazoles 1, benzoxazoles 2, oxazolium salts 3, and oxazole A -oxides 4 are fully conjugated compounds (Figure 1). In addition, the two mesoionic structures l,3-oxazolium-5-olates 5 and (l,3-oxazolium-4-olates) 6, commonly known as miinchnones and isomiinchnones, respectively, are also considered to be conjugated rings. There are five systems of hydroxyl-substituted oxazoles and they exist in their oxo forms the 2(3H)-, 2(5H)-, 4(5//)-, 5(2//)-, 5(4//)-oxazolones 7-11. Three forms of dihydrooxazoles are known 2,3-, 2,5-, and 4,5-dihydrooxazoles respectively 12-14. The fully saturated ring is called oxazoline 15. The monooxo derivatives are 2-oxazolidinone 16,4-oxazolidinone 17, and 5-oxazolidinone 18. The three variants of oxazolidinediones are 19-21 and the fully oxidized oxazolidi-netrione is 22. 

Oxazolone itself can be easily obtained from oxazolidinone through electrochemical reduction as described in CHEC-II(1996). A similar sequence was utilized in the synthesis of indole-substituted 2(3//)-oxazolone 244 (Scheme 71) <1997CPB733>. Electrochemical oxidation of 2-oxazolidinone in methanol gave a 4-methoxy oxazolidinone 241, which reacted with an organomagnesium indole reagent 242 in the presence of BF3-Et20, followed by... 

In many of these cases, the new chiral centre is generated in an achiral starting material (e.g., the oxazolone), whereas in others (e.g., the imidazolidinone) the starting compound is homochiral and cannot be recovered. However, the chiral auxiliary approach in which a homochiral reactant is recovered unchanged at the end of an asymmetric synthesis is illustrated in some of the examples in Scheme 6.7 (the Belokon and oxazolidinone methods are good examples). Many recent syntheses have used all these methods and close variants thereof. 

The intramolecular Pauson-Khand reaction of 2-oxazolone derivatives with a suitable alkyne appendage gave exclusively tricyclic oxazolidinones in quite satisfactory yields. 

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